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Bacillus subtilis and human adenylos...

University of Delaware., Department of Chemistry and Biochemistry.

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Bacillus subtilis and human adenylosuccinate lyase: I. Studies of two novel point mutations of ASL deficiency II. Effect of adjacent amino acids on the pK of His68 III. Studies with a new substrate analogue.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Bacillus subtilis and human adenylosuccinate lyase: I. Studies of two novel point mutations of ASL deficiency II. Effect of adjacent amino acids on the pK of His68 III. Studies with a new substrate analogue./
作者:	Sivendran, Sharmila.
面頁冊數:	147 p.
附註:	Adviser: Roberta F. Colman.
Contained By:	Dissertation Abstracts International69-01B.
標題:	Chemistry, Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoeng/servlet/advanced?query=3291767
ISBN:	9780549389620

Bacillus subtilis and human adenylosuccinate lyase: I. Studies of two novel point mutations of ASL deficiency II. Effect of adjacent amino acids on the pK of His68 III. Studies with a new substrate analogue.
Sivendran, Sharmila.

Bacillus subtilis and human adenylosuccinate lyase: I. Studies of two novel point mutations of ASL deficiency II. Effect of adjacent amino acids on the pK of His68 III. Studies with a new substrate analogue. - 147 p.

Adviser: Roberta F. Colman.

Thesis (Ph.D.)--University of Delaware, 2008.

Adenylosuccinate lyase is a homotetrameric enzyme that catalyzes two reversible reactions in the purine biosynthetic pathway. ASL deficiency results from several single point mutations which result in mild to severe mental retardation, muscle wasting and autistic features. Two novel point mutations, E80D and D87E, identified in an Australian patient, were characterized. Although one of the point mutations, E80D, is far from the active site, it seems to have a more detrimental effect on enzyme function as compared to D69E, which is found close to the active site.

ISBN: 9780549389620Subjects--Topical Terms:

1017722
Chemistry, Biochemistry.

Bacillus subtilis and human adenylosuccinate lyase: I. Studies of two novel point mutations of ASL deficiency II. Effect of adjacent amino acids on the pK of His68 III. Studies with a new substrate analogue.
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100 1 $a Sivendran, Sharmila. $3 1023450
245 1 0 $a Bacillus subtilis and human adenylosuccinate lyase: I. Studies of two novel point mutations of ASL deficiency II. Effect of adjacent amino acids on the pK of His68 III. Studies with a new substrate analogue.
300 $a 147 p.
500 $a Adviser: Roberta F. Colman.
500 $a Source: Dissertation Abstracts International, Volume: 69-01, Section: B, page: 0302.
502 $a Thesis (Ph.D.)--University of Delaware, 2008.
520 $a Adenylosuccinate lyase is a homotetrameric enzyme that catalyzes two reversible reactions in the purine biosynthetic pathway. ASL deficiency results from several single point mutations which result in mild to severe mental retardation, muscle wasting and autistic features. Two novel point mutations, E80D and D87E, identified in an Australian patient, were characterized. Although one of the point mutations, E80D, is far from the active site, it seems to have a more detrimental effect on enzyme function as compared to D69E, which is found close to the active site.
520 $a Mutagenesis studies of conserved residues in the active site have suggested that pK2 of the pH-Vmax profile reflects the ionization of histidines. Conserved residues close to His68 in the crystal structure, Asp69 and Arg310, when analyzed by mutagenesis, show that replacement of these charged residues with neutral residues results in greatly decreased activity, suggesting these residues are important for catalytic activity. When the same charge is maintained there is little change in pK2 (indicating the His68 proton is held tightly, as in WT), but when the charge is removed there is a decrease in pK2 suggesting the His68 proton is removed more easily. This shift in p K2 supports the previous postulate that His68 acts as the general acid.
520 $a ASL catalyzes two similar reactions, questioning whether the two substrates occupy the same or different active sites. Studies with a new substrate analogue, adenosine phosphonobutyric acid, 2'(3'), 5'-diphosphate, show the two substrates occupy the same active site. Binding studies with this substrate analogue demonstrate that B. subtilis ASL has negative and human ASL has positive cooperativity in binding ligand. Binding studies of B. subtilis ASL inactive mutants show that these mutants bind the substrate analogue similarly to WT, indicating the replaced amino acids are important for catalysis (kcat) and not for binding substrate. Serines in the signature sequence region of the fumarase superfamily of enzymes, when mutated to determine the effect of these residues on activity, show that human Ser289, B. subtilis Ser262 and Ser263 affect Vmax but not binding and that they may be interacting with the active sites.
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650 4 $a Chemistry, Biochemistry. $3 1017722
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710 2 $a University of Delaware. $b Department of Chemistry and Biochemistry. $3 1023449
773 0 $t Dissertation Abstracts International $g 69-01B.
790 $a 0060
790 1 0 $a Bahnson, Brian J. $e committee member
790 1 0 $a Burnside, Joan $e committee member
790 1 0 $a Colman, Roberta F., $e advisor
790 1 0 $a Riordan, Charles G. $e committee member
791 $a Ph.D.
792 $a 2008
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoeng/servlet/advanced?query=3291767